Uveitis is the third leading cause of blindness in the US. Generally, the standard therapy for the past 60 years is to treat uveitis with cortical steroid; however, 60% of uveitis patients will have at least another episode of uveitis, and about 18% will continue to suffer chronic uveitis. Steroid replacement therapy with biologics demands a significant commitment in resources and time by patients and physicians to find the most effective and tolerated biologic. As like with steroid therapy, biologics carry their own serious side-effects. The goal of these therapies is to suppress the inflammation long enough in the hope that an undefined regulating mechanism will take hold to suppress inflammation once the therapy is withdrawn. Therefore, development of a therapeutic approach that clearly does this has a great promise. This new therapeutic approach must activate immune regulation within the eye, actively promote immune tolerance, and reestablish ocular immune privilege. The endogenous neuropeptide alpha-Melanocyte Stimulating Hormone (?-MSH), a member of the highly conserved melanocortin family of peptides and receptors, is a potent suppressor of inflammation. Also, ?-MSH holds a central role in healthy eyes by helping to maintain ocular immune privilege. Preliminary studies using ?-MSH peptide therapy have shown that this treatment suppresses rodent models of autoimmune uveitis. Also, ?-MSH treatment appears to led to RPE cell recovery of immune regulating activity. It is through three melanocortin receptors that ?-MSH suppresses inflammation, and induces the immune system to regulate itself though induction of regulatory T cells. Our preliminary data show that receptor specific agonists to MC1r and MC5r both suppress EAU; however, it is through MC5r that ?-MSH mediates induction of immune regulation. This suggests a strong possibility that MC5r stimulation is the necessary for ?-MSH suppression of EAU, and the possibly of reactivating ocular immune privilege. Therefore, this proposal is to test the hypothesis that the therapeutic use of the neuropeptide ?-MSH in uveitic eyes will manipulate the immune response to suppress itself and restore the anti-inflammatory ocular microenvironment. This will be approached by answering two questions. 1) Is the suppression of EAU seen by ?-MSH therapy because of re-expression of the expected immune privilege mechanisms of aqueous humor and RPE? 2) Are specific melanocortin receptors required for ?-MSH suppression of EAU, and the re-expression or enhancement of the expected anti-inflammatory activity of ocular immune privilege? The results of this work will have a significant impact by showing that a new therapeutic direction for uveitis is possible, and that the new direction is to suppress inflammation, induce immune tolerance, and reestablish ocular immune privilege using the neuropeptide ?- MSH.